Absolute Protein-Protein Association Rate Constants from Flexible, Coarse-Grained Brownian Dynamics Simulations: The Role of Intermolecular Hydrodynamic Interactions in Barnase-Barstar Association
Absolute Protein-Protein Association Rate Constants from Flexible, Coarse-Grained Brownian Dynamics Simulations: The Role of Intermolecular Hydrodynamic Interactions in Barnase-Barstar Association
复制标题
DOI：
10.1016/j.bpj.2010.09.006
复制
发表时间：
2010-11-03
影响因子：
3.4
通讯作者：
Elcock, Adrian H.
中科院分区：
文献类型：
--
作者：
Frembgen-Kesner, Tamara;Elcock, Adrian H.
理论和计算长期以来一直被用来合理化蛋白质-蛋白质复合物的实验缔合速率常数，特别是布朗动力学（BD）模拟，已经成功地再现了野生型和突变蛋白质对的相对速率常数。然而，从以前的BD研究协会动力学失踪，一直是描述的流体动力学相互作用（His）之间，和内，扩散蛋白质。在这里，我们解决这个问题，严格包括他在BD模拟的barnase-barstar协会反应。我们首先表明，即使是非常简化的蛋白质的表示，涉及大约一个假原子的每三个残基的蛋白质，可以提供良好的再现的绝对关联速率常数的野生型和突变蛋白对。然后，我们表明，模拟，包括分子间的他也产生很好的估计的关联速率常数，但是，对于一个给定的反应标准，产量值减少了类似的35-80%，相对于那些在没有分子间的他。因此，在以前的BD模拟研究中忽略了分子间组氨酸，可能是导致以前获得的绝对速率常数有些高估的原因。因此，分子间组氨酸可能是一个重要的组成部分，包括在精确建模的大分子缔合事件的动力学。
Theory and computation have long been used to rationalize the experimental association rate constants of protein-protein complexes, and Brownian dynamics (BD) simulations, in particular, have been successful in reproducing the relative rate constants of wild-type and mutant protein pairs. Missing from previous BD studies of association kinetics, however, has been the description of hydrodynamic interactions (His) between, and within, the diffusing proteins. Here we address this issue by rigorously including His in BD simulations of the barnase-barstar association reaction. We first show that even very simplified representations of the proteins-involving approximately one pseudoatom for every three residues in the protein-can provide excellent reproduction of the absolute association rate constants of wild-type and mutant protein pairs. We then show that simulations that include intermolecular His also produce excellent estimates of association rate constants, but, for a given reaction criterion, yield values that are decreased by similar to 35-80% relative to those obtained in the absence of intermolecular HIs. The neglect of intermolecular His in previous BD simulation studies, therefore, is likely to have contributed to the somewhat overestimated absolute rate constants previously obtained. Consequently, intermolecular His could be an important component to include in accurate modeling of the kinetics of macromolecular association events.